美国哈佛医学院和布里格姆妇女医院 Vijay K. Kuchroo, Danyang He以及美国麻省理工学院和哈佛大学Aviv Regev共同合作，取得重要研究进展。他们发现IL-33-ST2-AKT信号轴的破坏通过抑制小胶质细胞的代谢适应和吞噬功能从而损害神经发育。该项研究成果发表在2021年1月3日出版的《免疫》杂志上。

在这项研究中，科研人员探究了在神经发育过程中细胞代谢是否调节小胶质细胞的功能。小胶质细胞线粒体的生物能量与发育中大脑的吞噬活动相关。具有不同代谢特征的小胶质细胞转录谱分析揭示了一种激活信号特征：IL-33信号轴与吞噬活性相关。IL-33或其受体ST2的遗传干扰会导致小胶质细胞营养不良、突触功能受损和行为异常。小胶质细胞中星形胶质细胞的 Il33 或编码 ST2 的 Il1rl1 的条件性缺失增加了癫痫发作的易感性。

从机制上讲，IL-33以AKT依赖的方式促进线粒体活性和吞噬作用。线粒体代谢和AKT活性在体内受到时间调控。因此，由IL-33-ST2-AKT信号转轴介导的小胶质细胞-星形细胞回路支持早期发育过程中的小胶质细胞代谢适应和吞噬功能，对神经发育和神经精神疾病有影响。

据介绍，为了适应大脑发育过程中不断变化的需求，小胶质细胞必须经历大量的形态、表型和功能的重编程。

附：英文原文

Title: Disruption of the IL-33-ST2-AKT signaling axis impairs neurodevelopment by inhibiting microglial metabolic adaptation and phagocytic function

Author: Danyang He, Heping Xu, Huiyuan Zhang, Ruihan Tang, Yangning Lan, Ruxiao Xing, Shaomin Li, Elena Christian, Yu Hou, Paul Lorello, Barbara Caldarone, Jiarui Ding, Lan Nguyen, Danielle Dionne, Pratiksha Thakore, Alexandra Schnell, Jun R. Huh, Orit Rozenblatt-Rosen, Aviv Regev, Vijay K. Kuchroo

Issue&Volume: 2021-01-03

Abstract: To accommodate the changing needs of the developing brain, microglia must undergosubstantial morphological, phenotypic, and functional reprogramming. Here, we examinedwhether cellular metabolism regulates microglial function during neurodevelopment.Microglial mitochondria bioenergetics correlated with and were functionally coupledto phagocytic activity in the developing brain. Transcriptional profiling of microgliawith diverse metabolic profiles revealed an activation signature wherein the interleukin(IL)-33 signaling axis is associated with phagocytic activity. Genetic perturbationof IL-33 or its receptor ST2 led to microglial dystrophy, impaired synaptic function,and behavioral abnormalities. Conditional deletion of Il33 from astrocytes or Il1rl1, encoding ST2, in microglia increased susceptibility to seizures. Mechanistically,IL-33 promoted mitochondrial activity and phagocytosis in an AKT-dependent manner.Mitochondrial metabolism and AKT activity were temporally regulated in vivo. Thus, a microglia-astrocyte circuit mediated by the IL-33-ST2-AKT signaling axissupports microglial metabolic adaptation and phagocytic function during early development,with implications for neurodevelopmental and neuropsychiatric disorders.

DOI: 10.1016/j.immuni.2021.12.001

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00534-3